Oxygen, angiogenesis, cancer and immune interplay in breast tumour microenvironment: a computational investigation

Abstract

Breast cancer is a challenging global health problem among women. This study investigates the intricate breast tumour microenvironment (TME) dynamics utilizing data from mammary-specific polyomavirus middle T antigen overexpression mouse models (MMTV-PyMT). It incorporates endothelial cells (ECs), oxygen and vascular endothelial growth factors (VEGF) to examine the interplay of angiogenesis, hypoxia, VEGF and immune cells in cancer progression. We introduce an approach to impute immune cell fractions within the TME using single-cell RNA-sequencing (scRNA-seq) data from MMTV-PyMT mice. We quantify our analysis by estimating cell counts using cell size data and laboratory findings from existing literature. We perform parameter estimation via a Hybrid Genetic Algorithm (HGA). Our simulations reveal various TME behaviours, emphasizing the critical role of adipocytes, angiogenesis, hypoxia and oxygen transport in driving immune responses and cancer progression. Global sensitivity analyses highlight potential therapeutic intervention points, such as VEGFs’ role in EC growth and oxygen transportation and severe hypoxia’s effect on cancer and the total number of cells. The VEGF-mediated production rate of ECs shows an essential time-dependent impact, highlighting the importance of early intervention in slowing cancer progression. These findings align with clinical observations demonstrating the VEGF inhibitors’ efficacy and suggest a timely intervention for better outcomes.

Keywords

• breast cancer
• tumour microenvironment
• angiogenesis
• mathematical modelling